FDA Approves PARP inhibitor Zejula for treatment of recurrent ovarian cancer.

courtesy:www.multivu.com

The U.S.Food and Drug Administration today approved Zejula (niraparib) for the maintenance treatment of epithelial ovarian, fallopian tube or primary peritoneal cancer in adult patients who have already responded well to platinum-based chemotherapy.

Richard Pazdur, M.D., acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research and director of the FDA’s Oncology Center of Excellence said “Maintenance therapy is an important part of a cancer treatment regimen for patients who have responded positively to a primary treatment. Zejula offers patients a new treatment option that may help delay the future growth of these cancers, regardless of whether they have a specific genetic mutation.”

According to an estimate by the National Cancer Institute more than 22,000 women will be diagnosed with these cancers in 2017 and more than 14,000 will die of these diseases.

Zejula is the first poly ADP-ribose polymerase (PARP) inhibitor to receive FDA approval to use without testing for BRCA mutation. It acts by preventing DNA repair by blocking an enzyme in the repair pathway.

The drug is niraparib and will be sold under the brand name Zejula by the manufacturer Tesaro (Waltham, Mass.).

FDA approved Zejula following results of a Phase III ENGOT-OV16/NOVA randomized trial of 553 patients who have already responded well to platinum-based chemotherapy. In addition, the patients were also tested for BRCA mutation although it does not require BRCA mutation or other biomarker testing. 

The study looked at the time for which the patients remained free from tumor recurrence irrespective of their BRCA status. Patients with BRCA mutation on Zejula did not have any recurrence for 21 months vs. 5.5 months for the same patient population taking a placebo. Patients who do not have BRCA mutation (n=350) on Zejula had 9.3 months of disease free survival compared to 3.9 months for patients on placebo.

Thus, the drug is more effective in patients who have the BRCA mutation but it can be given to patients who does not have the germline defect.

Partial trial results were published online December 1,2016 in the New England Journal of Medicine(NEJM).

Zejula have the usual side effects of chemotherapy drugs. Low blood counts, low platelets along with insomnia and high blood pressure are the most distressing side effects leading to discontinuation of drug in 15% of patients. It is contraindicated in pregnant and lactating mothers.

Zejula also received the ‘orphan drug status ‘by FDA because of its use in treatment of primary peritoneal cancer, a rare malignancy that is generally considered as ovarian-like. The orphan drug status is granted when a drug is used to treat rare disease.

The other two PARP inhibitors approved by FDA are olaparib (Lynparza, AstraZeneca) and rucaparib(brand name, Rubraca; Clovis Oncology, Boulder, Colo.) both are only used in patients with BRCA mutation and require testing for BRCA mutation.

Osteoporosis drug can prevent the development of breast cancer in women who are BRCA1 mutation carriers.

Individuals who carry a mutation in breast cancer susceptibility gene(BRCA1) are highly prone to develop breast cancer.  As compared to general population who have 8% chance of developing breast cancer, women who harbor this germline mutation have a 55-65% chance of developing breast cancer by the age 70.[1]

These women frequently undergo prophylactic risk reducing surgeries ( (bilateral prophylactic mastectomy and bilateral prophylactic salpingo-oophorectomy) to minimize the chances of developing breast cancer.[2]

Scientist around the world are long looking for chemoprevention to reduce the risk of cancer in BRCA1 mutation carriers. Currently Tamoxifen is in use for chemoprevention.  

 A recent paper published in Nature[3] offers a breakthrough for millions of next generation women with BRCA1 mutation carrier. Researchers are already considering it as ‘holy grail’ of breast cancer prevention.

Denosumab is a human monoclonal antibody for the treatment of osteoporosis. It is also a RANKL signaling inhibitor, RANK⁺ and RANK⁻  are two subsets of luminal progenitors present in the histological normal breast tissue of BRCA1 mutation carriers. RANK⁺ cells are highly proliferative, have grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. Denosumab inhibited the RANK⁺ signaling and stopped the progesterone induced proliferation of pre-neoplastic cells and also tissues from breast biopsies of BRCA1 mutation carriers. The same effect was also seen in mouse model of mammary tumorigenesis. Denosumab is already in use for treatment of osteoporosis and for patients with bone metastasis of breast cancer. 

Geoff Lindeman, a clinician-scientist at the Walter and Eliza Hall Institute and a co-author of the study said "Over the last few years, it has become increasingly clear from the work of several groups that RANK ligand, which switches on RANK, is an important regulator of cell growth in the breast. We have now been able to pinpoint the precise culprit cells and were very excited to see that they express the RANK protein."

As a part of pilot study three women were also treated with Denosumab and the results are encouraging days Dr. Lindeman.

Dr. Francisco Esteva (researcher at NYU Langone Medical Center and a part of the pilot study) and his colleagues are looking forward to conducting large scale clinical trials. "The new study does not change any management or clinical use of any drugs at this point, but it provides data that can be tested in a clinical trial," he said. "The data are compelling."

He also added that we are looking at least 10 years down the lane, but it offers hope for future generations of women.

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[1]http://ww5.komen.org/BreastCancer/InheritedGeneticMutations.html

[2] http://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet

[3] http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.4118.html#access